Steroid monohydrates, formulations containing same and method

ABSTRACT

A monohydrate of a steroid having the structure ##STR1## and the 1,2-dehydro derivatives thereof, is provided which monohydrate is in the form of a particulate material having a stable average particle size of less than about 20 microns. Cream and lotion formulations containing the steroid monohydrate and a method for forming the monohydrate are also provided.

This is a continuation of application Ser. No. 340,127, filed Jan. 18,1982 now U.S. Pat. No. 4,391,755.

FIELD OF THE INVENTION

The present invention relates to steroid monohydrates which have stableparticle sizes, to creams, lotions and other water-containingformulations containing such steriod monohydrates and to a method formaking such steroid monohydrates.

BACKGROUND OF THE INVENTION

It is known that cortisone acetate exists in several polymorphic forms,Collard, R. E. (1961), Pharm. J., 186, 113-117 published photographs of4μ particles of cortisone acetate which changed to particles of up to100μ by suspension in water for less than 24 hours. Carless, et al.,"Dissolution and crystal growth in aqueous suspensions of cortisoneacetate", J. Pharm. Pharmac., 1968, 20, 630-638, describe a techniquefor limiting crystal growth of cortisone acetate by mixing 100 mgmicronized cortisone acetate with 0.5 ml of 5% v/v solution of NonidetP42 (Shell Oil Co. non-ionic wetting agent which has approximately 27%of a polyethylene oxide condensate as active material) in 0.9% w/vsolution of sodium chloride. This was then gradually diluted with 9.5 mlof the Nonidet-sodium chloride solution. The cortisone acetate changesto the water stable form with very little change in size distribution,Carless, et al. "Effect of crystal form, cortisone alcohol and agitationon crystal growth of cortisone acetate in aqueous suspensions", J.Pharm. Pharmac., 1968, 20, 639-645.

U.S. Pat. No. 3,937,720 to Varma, et al. discloses steroids of thegeneral structure ##STR2## and the 1,2-dehydro derivatives thereof,wherein R₁ is chlorine, fluorine, or hydroxy and R'₁ is hydrogen or R₁and R'₁ together are ═O; R₂ is hydrogen or halogen; R₃ is hydrogen,methyl, or fluorine; R₄ is hydrogen, hydroxy, ##STR3## or halogen; R₅and R₆ are the same or different and are hydrogen, alkyl, alkylthio,alkoxy, carboalkoxy, formyl, ##STR4## hydroxy, halogen, phenyl or cyano,with the proviso that when R₅ and R₆ are different, one of R₅ and R₆ ishydrogen, included within the above are 21-(acetyloxy)-9-fluoro1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno-[16α,17-b]naphthalene-3,20-dione and (11β,16β)-9-fluoro-1',2',3',4'-tetrahydro-11,21-dihydroxypregna-1,4-dieno[16,17-b]naphthalene-3,20-dione.It has been found that steroids as defined herein when micronized andsuspended in water undergo a transformation to their monohydrate formwithin several hours with a concomitant increase in particle size. Infact, the micronized particles upon hydration grow from an averageparticle size of less than 20 microns and usually less than 10 micronsinto long needle-like crystals about 50 to 75 microns in length. Theselong crystals are undesirable because their smaller surface area mayreduce dissolution rate and bioavailability.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a steroid inthe form of its monohydrate which has a stable average particle size ofless than about 20 microns and has a dissolution rate andbioavailability equivalent to the steroid in its anhydrous form.

The steroid monohydrate of the invention is a monohydrate of a steroidhaving the structure ##STR5## and the 1,2-dehydro derivative thereof,wherein R₁ is chlorine, fluorine or hydroxy and R'₁ is hydrogen or R₁and R'₁ together are ═O; R₂ is hydrogen or halogen; R₃ is hydrogen,methyl or fluorine; R₄ is hydrogen, hydroxy, ##STR6## or halogen, and R₅and R₆ are the same or different and are hydrogen, alkyl, alkythio,alkoxy, carboalkoxy, formyl, ##STR7## hydroxy, halogen, phenyl or cyano,with the proviso that when R₅ and R₆ are different, one of R₅ and R₆ ishydrogen.

The above steroids are disclosed in and prepared as described in U.S.Pat. No. 3,937,720 which is incorporated herein by reference.

In addition, in accordance with the present invention, a method isprovided for forming the steroid monohydrate of stable particle size asdescribed above, which method includes the steps of micronizing thesteroid, in anhydrous form, to reduce average particle size to belowabout 20 microns, preferably below about 10 microns and optimally belowabout 5 microns, introducing the micronized anhydrous steroid into waterto form a suspension containing from about 5 to about 20% by weightsteroid and preferably from about 10 to about 15% by weight steroid, andallowing the steroid to remain in suspension for a minimal period of 0.1hour and preferably from about 0.5 to about 4 hours, to thereby form themonohydrate of the steroid in the form of long needle-like crystalshaving an average length greater than 40 to 50 microns or more, reducingthe average particle size of the monohydrate crystals, for example, bypassing the suspension through a high energy colloid mill, to belowabout 25 microns, to preferably below about 10 microns, and optimallybelow about 5 microns, to produce the steroid monohydrate in a formhaving a stable crystal size. Furthermore, emulsification of the aqueoussuspension of such monohydrate with other excipients as describedhereinafter results in a cream or lotion wherein the steroid monohydratewill experience no further crystal growth.

The high energy colloid mill or similar apparatus employed in reducingthe average particle size of the monohydrate crystals will preferably beof the impact type, that is a stream of the aqueous suspension of thesteroid monohydrate will be impacted against a static plate under highpressures of 5000 psi or more. Grinding mechanisms, ball mills,homomixer, and hand homogenizers are not effective in breaking thesuspended hydrate particles.

An alternative method for forming the steroid monohydrate is alsoprovided, which method includes the steps of micronizing the steroid, inanhydrous form, to reduce average particle size to below about 20microns, preferably below about 10 microns and optimally below about 5microns, subjecting the micronized anhydrous steroid to a relativehumidity of higher than about 40%, and preferably higher than about 80%,for a period of at least about 4 hours, and preferably at least about 24hours to form a monohydrate having a crystal size and shape whichremains in the desirable range during this hydration from the vapourphase; no further comminution is required.

One embodiment of the above alternative method, which is a preferredembodiment, includes the steps of forming a thin layer of the micronizedanhydrous steroid (such as less than 1 cm) such as on a tray or otherflat surface, providing one, two or more beakers of water in thevicinity of the layer of steroid, enclosing the atmosphere surroundingthe steroid and beakers such as with a piece of plastic or plastic bag,and allowing the assembly to remain for at least 1/2 day and preferablyat least 1 day, preferably at ambient temperature, to thereby form thesteroid monohydrate without any growth in particle size.

The steroid monohydrate so-produced having a stable crystal size may beincorporated into a cream or lotion vehicle without any further crystalgrowth.

Furthermore, in accordance with the present invention, cream and lotionsteroid formulations are provided wherein a steroid monohydrate having astable average particle size of less than about 20 microns, preferablyless than about 10 microns, and optimally less than about 5 microns isincluded.

The steroid monohydrate will be present in an amount of from about 0.001to about 3% by weight, and preferably from about 0.025 to about 0.2%based on the total weight of the composition, depending upon the steroidmonohydrate employed and its solubility in the vehicle employed.

Examples of vehicles which may be employed include ricinoleates, such ascastor oil as disclosed in U.S. Pat. No. 4,408,310, polyol vehicles,such as polyethylene glycol and/or propylene glycol as disclosed in U.S.Pat. Nos. 3,892,856 and 3,892,857, and in copending U.S. applicationSer. No. 325,708, filed Nov. 30, 1981, all of the above beingincorporated herein by reference.

The cream or lotion will also contain antioxidants,emulsifier-thickeners, preservatives and anti-foaming-anti-whiteningagents and other conventional cream or lotion ingredients, examples ofwhich are disclosed in U.S. Pat. Nos. 3,892,856, 3,892,857 and 4,048,310as well as application Ser. No. 325,708 referred to above.

The steroid monohydrates of the invention are physiologically activesubstances which possess glucocorticoid and antiinflammatory activityand hence can be used in lieu of known glucocorticoids in the treatmentof rheumatoid arthritis, for which purpose they can be administered inthe same manner as hydrocortisone, for example, the dosage beingadjusted for the relative potency of the particular steroid. Inaddition, the steroid monohydrate of this invention can be usedtopically in lieu of known glucocorticoids in the treatment of skinconditions such as dermatitis, psoriasis, sunburn, neurodermatitis,eczema, and anogenital pruritus.

When given orally, the compounds of this invention may be used in adosage range of 0.1 to 200 milligrams, preferably 0.3 to 100 milligrams.If administered topically, the compounds of this invention may be usedin the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% byweight, in a conventional cream or lotion.

The following Examples represent preferred embodiments of the invention.All temperatures are expressed in degrees Centigrade.

EXAMPLE 1

Preparation of monohydrate of21-(acetyloxy)-9-fluoro-1',2'3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene-3,20-dionehaving stable particle size.

21-[Acetyloxy)-9-fluoro-1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene-3,20-dione(60 gm) was run through a Trost Mill Model Gem-T (Garlock, Newton, Pa.)micronizing machine to reduce average particle size to less than about 4microns, that is 2-3 microns.

In order to establish that the above steroid undergoes formation of themonohydrate with concomitant crystal growth when introduced into water,the following experiments were carried out.

A. A portion of the micronized anhydrous steroid (2-3 micron particlesize) was suspended in water and upon examination after an hour, theparticle size distribution changed dramatically to long thin needlesabout 50 microns in length. Upon TGA (thermal gravimetric analysis)analysis and Karl-Fischer analysis of water content, it was determinedthat a monohydrate of the steroid formed in solution. It was also foundthat polysorbate 60, either used to wet the micronized steroid first oradded to the suspension afterwards, facilitated hydrate formation whileproducing crystals exhibiting increased geometric symmetry.

B. A portion of the micronized anhydrous steroid was incorporated into acream formulation (10% steroid) and after about 4 hours, it was observedthat a significant portion of the steroid was converted to themonohydrate with concomitant crystal growth in the cream itself.

C. In accordance with the invention, a monohydrate of the above steroidhaving a stable average particle size of less than 10 microns wasprepared as described below.

50 mg. of micronized steroid (as described above) was wetted by 3 ml of0.5% polysorbate 60 and then added to 500 ml of water. The resultingaqueous suspension was recycled through a Manton-Gaulin Homogenizerunder 6000 psi pressure for about 5 minutes. Microscopic examination ofthe resulting suspension, immediately and 5 days later, showed noparticles larger than 10 microns and the majority was less than 5microns in size. Before comminution, the micronized steroid had formed amonohydrate characterized by needle-like crystals about 50 to 75 micronsin length.

EXAMPLE 2

A steroid cream of the following composition is prepared as describedbelow.

    ______________________________________                                        Ingredient           Amount                                                   ______________________________________                                        Steroid monohydrate prepared as                                                                    0.1        gm                                            in Example 1 in 10% aqueous                                                   suspension (average particle                                                  size less than 10 microns)                                                    Polysorbate 60       8          gm                                            Cetyl alcohol        10         gm                                            Myristyl stearate    5          gm                                            Isopropyl palmitate  10         gm                                            Methyl paraben       0.2        gm                                            Water q.s.           100        gm                                            ______________________________________                                    

(1) The cetyl alcohol, myristyl stearate and isopropyl palmitate andpolysorbate 60 are heated to about 90° C. and melted.

(2) Add appropriate amount water to the mixture of (1), stir well, allowto cool down to 30°-40° C. gradually

(3) Use a small amount of water and polysorbate to wet the steroidmonohydrate to form a smooth paste.

(4) Add the steroid to the cream base prepared under (2)

The above cream has excellent size stability even after prolongedstorage.

EXAMPLE 3

A liter of lotion of the following composition is prepared as describedbelow.

    ______________________________________                                        Ingredient                 Amount                                             ______________________________________                                        Steroid monohydrate of Example 1 (if 10% aqueous                                                         1      gm                                          suspension was used, need 10 ml)                                              Cetyl alcohol              32     gm                                          Stearyl alcohol            21     gm                                          Polysorbate 20             23     gm                                          Sorbitan monopalmitate     53     gm                                          Antifoam A silicone        0.1    gm                                          Propylene glycol           150    gm                                          Water q.s. to make         1      liter                                       ______________________________________                                    

(1) The cetyl alcohol, stearyl alcohol, polysorbate 20 and sorbitanmonopalmitate are heated to about 85° C. and melted.

(2) A portion of the propylene glycol is added to the water and thesolution is heated to about 85° C.

(3) Mixtures (1) and (2) are combined at about 85° C., the Antifoam ASilicone is added, and the mixture is stirred rapidly at 85° C. to forma lotion, which is cooled to room temperature.

(4) The steroid monohydrate is dispersed into the remaining propyleneglycol and blended with the lotion vehicle from (3) at room temperature.

The steroid monohydrate is found to retain its particle size stabilityeven upon prolonged storage.

EXAMPLES 4 TO 7

A steroid monohydrate cream formulation having a stable particle sizeand the composition set out below is prepared as follows.

    ______________________________________                                                     Example  Example  Example                                                                              Example                                 % by weight  4        5        6      7                                       Steroid Monohydrate                                                                        0.2%,    0.1%,    0.05%, 0.025%,                                 ______________________________________                                                   per 100 gm                                                         Steroid monohydrate                                                                        0.2    g     0.1  g   0.05 g   0.025                                                                              g                            of Example 1 (average                                                         particle size less                                                            than 10 microns)                                                              Glyceryl Stearates                                                                         7.0    g     7.0  g   7.0  g   7.0  g                            Cetyl Alcohol, N.F.                                                                        5.0    g     5.0  g   5.0  g   5.0  g                            White Wax, USP                                                                             3.0    g     3.0  g   3.0  g   3.0  g                            Isopropyl Palmitate                                                                        3.0    g     3.0  g   3.0  g   3.0  g                            Tween 60     4.0    g     4.0  g   4.0  g   4.0  g                            Propylene Glycol,                                                                          15.0   g     15.0 g   15.0 g   15.0 g                            USP                                                                           Dimethicone 350                                                                            1.0    g     1.0  g   1.0  g   1.0  g                            Citric Acid  0.02   g     0.02 g   0.02 g   0.02 g                            Anhydrous, USP                                                                Purified Water, USP                                                                        100    g     100  g   100  g   100  g                            To make                                                                       ______________________________________                                    

The 0.2% potency formulation is prepared as follows:

1. In a suitable stainless steel or glass lined container the glycerylstearates, cetyl alcohol, white wax and isopropyl palmitate are heatedand melted at 90°-95° C. and mixed until homogeneous.

2. In a separate stainless steel or glass lined container the citricacid, tween 60, and a portion of the propylene glycol in the purifiedwater are added, heated to 90°-95° C. and stirred until all solids aredissolved.

The hot oil phase in Step No. 1 is added to the hot aqueous phase inStep No. 2 and agitation is continued for ca 30 minutes whilemaintaining the mixture of 90°-95° C.

The Dimethicone 350 (silicone DC 200 fluid) is added to the batch withcontinuous agitation and the batch is then cooled to ca 25°-28° C. In aseparate container steroid monohydrate is dispersed in the remainingportion of the propylene glycol. The dispersion is agitated orhomogenized until smooth. The monohydrate dispersion is added to themain batch of cream base and mixing is continued until homogeneous usingslow speed agitation. Sufficient purified water is then added to bringthe batch to final weight and the batch is stirred until homogeneous.

Each of the lower potency creams 0.1%, 0.05% and 0.025% are prepared bydilution of the 0.2% cream with similar cream containing no steroid. Thedilutions are prepared by hand levigation with a spatula on a pill tileusing the geometric dilution method.

All of the cream formulations of Examples 4 to 7 are found to haveexcellent particle size stability.

EXAMPLE 8

In a manner similar to that described in Example 1, a monohydrate of(11β,16β)-9-fluoro-1',2',3',4'-tetrahydro-11,21-dihydroxypregna-1,4-dieno[16,17-b]naphthalene-3,20-dioneis formed having an average stable particle size of less than 10microns.

EXAMPLE 9

A cream formulation is prepared as described in Example 2 except thatthe monohydrate of Example 8 is employed in place of the Example 1monohydrate.

The so-formed cream formulation has excellent steroid particle sizestability.

EXAMPLE 10

A lotion formulation is prepared as described in Example 3 except thatthe monohydrate of Example 8 is employed in place of the Example 1monohydrate.

The so-formed lotion has excellent steroid particle size stability.

EXAMPLES 11 TO 14

A steroid monohydrate cream formulation having a stable particle sizeand the composition set out below is prepared as described in Examples4-7.

    ______________________________________                                                     Example  Example  Example                                                                              Example                                 % by weight  11       12       13     14                                      Steroid Monohydrate                                                                        0.2%,    0.1%,    0.05%, 0.025%,                                 ______________________________________                                                   per 100 gm                                                         Steroid monohydrate                                                                        0.2    g     0.1  g   0.05 g   0.025                                                                              g                            of Example 8 (average                                                         particle size less                                                            than 10 microns)                                                              Glyceryl Stearates                                                                         7.0    g     7.0  g   7.0  g   7.0  g                            Cetyl Alcohol, N.F.                                                                        5.0    g     5.0  g   5.0  g   5.0  g                            White Wax, USP                                                                             3.0    g     3.0  g   3.0  g   3.0  g                            Isopropyl Palmitate                                                                        3.0    g     3.0  g   3.0  g   3.0  g                            Tween 60     4.0    g     4.0  g   4.0  g   4.0  g                            Propylene Glycol,                                                                          15.0   g     15.0 g   15.0 g   15.0 g                            USP                                                                           Dimethicone 350                                                                            1.0    g     1.0  g   1.0  g   1.0  g                            Citric Acid  0.02   g     0.02 g   0.02 g   0.02 g                            Anhydrous, USP                                                                Purified Water, USP                                                                        100    g     100  g   100  g   100  g                            To make                                                                       ______________________________________                                    

What is claimed is:
 1. The steroid monohydrate having an averageparticle size of less than about 20 microns having the structure##STR8## and the 1,2-dehydro derivative thereof, wherein R₁ is chlorine,fluorine or hydroxy and R'₁ is hydrogen or R₁ and R'₁ together are ═O;R₂ is hydrogen or halogen; R₃ is hydrogen, methyl or fluorine, R₄ ishydrogen, hydroxy, ##STR9## or halogen; and R₅ and R₆ are the same ordifferent and are hydrogen, alkyl, alkylthio, alkoxy, carboalkoxy,formyl, ##STR10## ##STR11## hydroxy, halogen, phenyl or cyano, with theproviso that when R₅ and R₆ are different, one of R₅ and R₆ is hydrogen,which monohydrate is in the form of a particulate material having astable average particle size of less than about 20 microns, prepared bythe process which includes the steps of micronizing the steroid inanhydrous form to reduce average particle size to below about 20microns, introducing the micronized anhydrous steroid into water to forma suspension containing from about 5 to about 20% by weight steroid,allowing the steroid to remain in suspension for at least 0.1 hour tohydrate the steroid to form the corresponding monohydrate and causecrystal growth, and reducing the average particle size of the crystalsof hydrated steroid suspended in water to below about 20 microns to formparticles of steroid monohydrate having a relatively stable crystalsize.
 2. The steroid as defined in claim 1 wherein the average particlesize of the crystals of hydrated steroid is in the range of from about40 to 90 microns and is reduced to an average particle size of less thanabout 20 microns.
 3. The steroid as defined in claim 1 wherein crystalsof hydrated steroid are reduced to an average particle size of less thanabout 10 microns.
 4. The steroid as defined in claim 3 wherein crystalsof hydrated steroid are reduced to an average particle size of less thanabout 5 microns.
 5. The steroid as defined in claim 1 wherein theanhydrous steroid is21-(acetyloxy)-9-fluoro-1',2',3',4'-tetrahydro-11β-hydroxypregna-1,4-dieno[16α,17-b]naphthalene-3,20-dione.6. The steroid as defined in claim 1 wherein the anhydrous steroid is(11β,16β)-9-fluoro-1',2',3',4'-tetrahydro-11,21-dihydroxypregna-1,4-dieno-[16,17-b]naphthalene-3,20-dione.7. The steroid as defined in claim 1 wherein the micronized anhydroussteroid is allowed to remain in the water for a period of from about 0.1to about 4 hours to allow for formation of a monohydrate and crystalgrowth.
 8. The steroid as defined in claim 1 wherein the steroid inanhydrous form is micronized to an average particle size of below about5 microns.
 9. The steroid monohydrate having an average particle size ofless than 20 microns having the structure ##STR12## and the 1,2-dehydroderivative thereof, wherein R₁ is chlorine, fluorine or hydroxy and R'₁is hydrogen or R₁ and R'₁ together are ═O; R₂ is hydrogen or halogen; R₃is hydrogen, methyl or fluorine; R₄ is hydrogen, hydroxy, ##STR13## orhalogen; and R₅ and R₆ are the same or different and are hydrogen,alkyl, alkylthio, alkoxy, carboalkoxy, formyl, ##STR14## ##STR15##hydroxy, halogen, phenyl or cyano, with the proviso that when R₅ and R₆are different, one of R₅ and R₆ is hydrogen, which monohydrate is in theform of a particulate material having a stable average particle size ofless than about 20 microns, prepared by the process which includes thesteps of micronizing the steroid in anhydrous form and subjecting themicronized anhydrous steroid in a relative humidity of higher than 40%for a period of at least about 4 hours to form a monohydrate of thesteroid while controlling and limiting crystal size of the steroidmonohydrate.
 10. The steroid as defined in claim 9 wherein the anhydroussteroid is micronized to an average particle size of 10 microns or less.11. The steroid as defined in claim 9 wherein the micronized anhydroussteroid is in the form of a thin layer as it is subjected to the highrelative humidity.
 12. The steroid as defined in claim 10 wherein themicronized anhydrous steroid is subjected to the high relative humidityfor a mineral period of about one day.